EP0009425A1 - Dérivés de la naphtyridine et compositions pharmaceutiques les contenant - Google Patents

Dérivés de la naphtyridine et compositions pharmaceutiques les contenant Download PDF

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Publication number
EP0009425A1
EP0009425A1 EP79400587A EP79400587A EP0009425A1 EP 0009425 A1 EP0009425 A1 EP 0009425A1 EP 79400587 A EP79400587 A EP 79400587A EP 79400587 A EP79400587 A EP 79400587A EP 0009425 A1 EP0009425 A1 EP 0009425A1
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EP
European Patent Office
Prior art keywords
compound
naphthyridine
ethyl
compounds
piperazinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP79400587A
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German (de)
English (en)
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EP0009425B1 (fr
Inventor
Jun-Ichi Matsumoto
Yoshiyuki Takase
Yoshiro Nishimura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratoire Roger Bellon SA
Dainippon Pharmaceutical Co Ltd
Original Assignee
Laboratoire Roger Bellon SA
Dainippon Pharmaceutical Co Ltd
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Priority claimed from JP10423578A external-priority patent/JPS5531042A/ja
Priority claimed from JP15793978A external-priority patent/JPS5583785A/ja
Priority claimed from JP16209578A external-priority patent/JPS5592385A/ja
Application filed by Laboratoire Roger Bellon SA, Dainippon Pharmaceutical Co Ltd filed Critical Laboratoire Roger Bellon SA
Publication of EP0009425A1 publication Critical patent/EP0009425A1/fr
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Publication of EP0009425B1 publication Critical patent/EP0009425B1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C07D213/77—Hydrazine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to novel naphthyridine derivatives having high antibacterial activities, their intermediates, and also to their use as medicines, especially as antibacterial agents.
  • the present invention provides 1,8-naphthyridine compounds of the following formula wherein X is a halogen atom, especially a fluorine atom , R 1 is an ethyl or vinyl group, and R 2 is a hydrogen atom or a lower alkyl group ; and nontoxic salts thereof.
  • lower alkyl group either in itself or as part of other groups denotes an alkyl group containing 1 to 6 carbon atoms.
  • the salts of the naphthyridine compounds (I) are formed between the naphthyridine compounds (I) and acids or bases.
  • the acids may be various inorganic and organic acids, and examples of suitable acids are hydrochloric acid, acetic acid, lactic acid, succinic acid,lactobionic acid, and methanesulfonic acid.
  • the bases may be any inorganic or organic bases capable of forming salts with the carboxyl group of the compounds (I), and examples of suitable bases are metal hydroxides such as sodium or potassium hydroxide, and metal carbonates such as sodium or potassium carbonate.
  • Especially preferred salts of the compounds (I) are the hydrochlorides or methanesulfonates.
  • the naphthyridine compounds (I) may form as hydrates. These hydrates are also embraced by the naphthyridine compounds of the present invention which are represented by formula (I).
  • Another object of this invention is to provide a pharmaceutical composition containing such a novel naphthyridine compound.
  • Still another object of this invention is to provide a therapeutical use of these novel compounds.
  • compound 1 and its salts are most valuable as antibacterial agents.
  • the compound 1 and its salts exhibit very high antibacterial activities both in vitro and in vivo tests against Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa. Since they have extremely low toxicity, they are useful for the treatment of not only urinary tract infections caused by various Gram-positive and Gram-negative bacteria but also systemic infections caused by these bacteria.
  • compound 2 and its salts are valuable as antibacterial agents.
  • the lower alkyl esters of compounds 1 and 2 exhibit fairly high antibacterial activities in vivo. These esters are useful not only as antibacterial agents but also as intermediates for the synthesis of compounds 1 and 2.
  • R 1 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or an acetyl group
  • R 2 is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a benzyl group or a vinyl group
  • R 3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • Japanese Laid-Open Patent Publication No. 83590/ 77 discloses 6-nitro-1,8-naphthyridine derivatives of the following formula
  • -N(R)(R') is a member selected from the group of amino, substituted anilino, alkylamino, (cyclo)alkylamino, dialkylaminoalkylamino, hydroxyalkylamino, di- alkylamino, alkylallylamino, alkylcycloalkyl- amino, dihydroxyalkylamino, pyrrolidino, piperi- dino, morpholino, and piperazino, and each of R 1 and R 2 is lower alkyl.
  • the compounds of formula (I) can be synthesized, for example, by the following processes (1) and (2).
  • acyl group as R 3 examples include formyl, acetyl, trifluoroacetyl, benzyloxycarbonyl, t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, vinyloxycarbonyl, ethoxycarbonyl, and ⁇ -(p-toluenesulfonyl)ethoxycarbonyl.
  • Any known ethylating agents can be used. Specific examples include ethyl halides such as ethyl iodide and ethyl esters such as diethyl sulfate, ethyl p-toluenesulfonate, or triethyl phosphate.
  • This reaction is generally carried out by reacting the compound (a) with a stoichiometric amount of the ethylating agent in an inert solvent at an elevated temperature of, say, 25°C to 150°C.
  • the ethylating agent may be used in excess.
  • the solvent examples include ethanol, dioxane, methyl cellosolve, dimethylformamide, dimethyl sulfoxide, and water.
  • an acid- acceptor for example a base such as an alkali metal carbonate, an alkali metal hydroxide, an alkali metal alkoxide, sodium hydride, pyridine, triethylamine, and benzyltrimethylammonium hydroxide.
  • the reaction is carried out by heating the compound (b) in the presence of a catalyst such as a base.
  • a catalyst such as a base.
  • the catalyst are ordinary bases such as potassium bicarbonate, alkali metal hydroxides, alkali metal carbonates, metal hydrides such as sodium hydride, alkali metal alkoxides such as sodium ethoxide, sodium methoxide or potassium tert.-butoxide, pyridine, collidine, and benzyltrimethylammonium hydroxide.
  • the reaction temperature is usually 50°C to 270t.
  • the reaction proceeds in the absence of solvent, but preferably, it is carried out in an inert solvent.
  • the solvents are water, alcohols, dimethylformamide, dimethylsulfoxide, diethyl ether, benzene, dioxane, tetrahydrofuran, and pyridine.
  • the compounds of the present invention prepared in the above process can be isolated and purified by usual methods.
  • the compounds (I) can be obtained in the free state or in the form of a salt depending upon theselection of the starting materials and the reaction conditions.
  • the compounds (I) can be converted to pharmaceutically acceptable salts by treating them with an acid or a base.
  • the acid may be a variety of organic and inorganic acids, examples of which are hydrochloric acid, acetic acid, lactic acid, succinic acid, lactobionic acid, oxalic acid and methanesulfonic acid.
  • novel 1,8-naphthyridine derivatives of this invention have excellent antibacterial activities and low toxicity. Accordingly, these compounds can be used as drugs for the treatment or prevention of bacterial infections of warm- blooded animals including man.
  • the dosage of the compound [I] or its salt of this invention in administration to man should be adjusted according to the age, body weight and condition of the patient, the administration route, the number of administrations, etc.
  • the dosage for adults is 0.1 to 7 g/day, preferably 0.2 to 5 g/day.
  • the compounds of this invention may be used as medicines, for example, in the form of pharmaceutical preparations containing them in admixture with an organic or inorganic pharmaceutically acceptable solid or liquid adjuvants suitable for oral or topical administration.
  • Pharmaceutically acceptable adjuvants are substances that do not react whith the compounds of this invention. Examples are water, gelatin, lactose, starch, cellulose (preferably, microcrystalline cellulose), carboxymethyl cellulose, methyl cellulose, sorbitol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gums, propylene glycol, polyalkylene glycols, methylparaben and other known medicinal adjuvants.
  • the pharmaceutical preparations may be powder, granules, tablets, ointments, suppositories, creams, capsules, etc. They may be sterilized, and/or contain assistants such as preserving, stabilizing or wetting agents. They may further contain other therapeutically valuable substances according to the purpose of medication.
  • Examples 1 to 6 illustrate processes for the preparation of the compounds (I) or their salts of this invention.
  • Examples 7,8 and 9 show processes for the preparation of starting compounds.
  • Example 10 shows a process for preparation of a compound which is new, and is outside the scope of this invention as controls.
  • Examples A to G show the pharmacological activities of the compounds (I) and their salts of this invention in comparison with those of compounds which are outside the scope of this invention.
  • Examples H and J show the preparation of pharmaceuticals containing the compound (I) of this invention.
  • Ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbaxyl- ate (lg) was suspended in dimethylformamide (10 ml) and to the suspension was added potassium carbonate (0.53g). After the mixture was kept at 60°C for 10 minutes with stirring, ethyl iodide (1.2g) was added to the solution. The mixture was stirred for 2 hours at 60 - 70°C. The reaction mixture was concentrated to dryness under reduced pressure, and water was added to the residue. After extraction with chloroform, the chloroform extract was dried over anhydrous potassium carbonate.
  • the carboxylic acid (0.2g) thus obtained was dissolved in 5% hydrochloric acid, and the solution was concentrated to dryness under reduced pressure. The residue was crystallized from water to give a hydrochloride of the carboxylic acid (0.21g). m.p. above 300°C.
  • the above free carboxylic acid (0.2g) was dissolved in 7% methanesulfonic acid solution under heating. After cooling, the precipitate was recrystallized from diluted methanol to give a methanesulfonic acid salt of the carboxylic acid (0.22g), mp. above 300° (dec.).
  • 6-chloro-1-ethyl-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid hydrochloride (m.p. above 300°C) was obtained from ethyl 6-chloro-7-(4-ethoxycarboxyl-1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate by the same procedure as described in Example 1.
  • Ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-tri- fluoro-acetyl-l-piperazinyl)-1,8-naphthyridine-3-carboxylate was treated with ethyl iodide and potassium carbonate in dimethylformamide by the same procedure as described in Example 1 to form ethyl l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-trifluoroacetyl-1-piperazinyl)-1,8-naphthyridine-3-carboxylate.
  • This product was hydrolyzed by treating with aqueous potassium carbonate in a mixture of chloroform and methanol to give ethyl 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate, m.p. 150 - 151°C.
  • Ethyl l-(2-chloroethyl)-7-(4-ethoxycarboxyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (2027 g) was dissolved in ethanol (15 ml) by heating, and to the solution was added a solution of potassium hydroxide (0.84g) in ethanol (15 ml). The resulting solution was heated to reflux for 2 hours with stirring. The resulting crystals were collected by filtration and washed with ethanol. The crystals were then dissolved in 20 ml of water by heating, and the solution was adjusted to pH 4 - 5 with 10% acetic acid.
  • the carboxylic acid (0.2g) was mixed with a small amount of concentrated hydrochloric acid, and the resulting hydrochloride was collected by filtration. It was recrystallized from ethanol to give a hydrochloric acid salt of the carboxylic acid (0.21g), m.p. 290°C (dec.).
  • 2,6-Dichloro-3-nitropyridine (30g) was reacted with N-ethoxycarbonylpiperazine (25.8g) and triethylamine (15.7g) in chloroform at -10°C for 1 hour to give 6-chloro-2-(4-ethoxy-carbonyl-1-piperazinyl)-3-nitropyridine.
  • the product without further purification, was heated with 15% ethanolic ammonia (320ml) in a sealed tube at 120 - 125°C for 4 hours to give 6-amino-2-(4-ethoxy-carbonyl-l-piperazinyl)-3-nitropyridihe (34.4g) (mp 132 - 134°C).
  • the amino compound (21.4g) was treated with a mixture of acetic anhydride (35ml) and acetic acid (35ml) at 80-90°C for 30 minutes.
  • the resulting 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine (23.3g) was hydrogenated in the presence of 5% palladium- carbon in acetic acid to yield 3-amino-6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)pyridine, which without further purification, was dissolved in a mixture of ethanol ( 50 ml) and 42% tetrafluoroboric acid (30 ml) and to this stirred solution was added a solution of isoamyl nitrite (707g) in ethanol below 0°C.
  • the 3-fluoro derivative (22,6g) was hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1 : 2 v/v) to give 6-amino-2-(4-ethoxycarbonyl-1-piperazinyl)-3-fluoro- pyridine.
  • This compound was treated with diethyl ethoxymethylene-malonate at 130 - 140°C to give diethyl N-(2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoro-6-pyridinyl)aminomethylenemalonate (30.6g) (mp 144 - 145°C) and then the product (30g was cyclized by heating at 255°C to give ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (20 g) (mp 27 9 - 281°C).
  • Example 9 Preparation of a starting compound ethyl7-(4-acetyl-1-piperazinyl)-6-chloro-1-(2-chloro-ethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate-.
  • Ethylene bromohydrine (12.6 g) was then added to the suspension.
  • the resulting mixture was heated at 80 degrees centigrade for an additional one hour with stirring and, after cooling, filtered to remove an insoluble material.
  • the filtrate was concentrated to dryness under reduced pressure. A small amount of water was added to the residue to yield a crystalline product which was collected and washed with water to give 11.Og of ethyl 7-(4-acetyl-l-piperazinyl)-6-chloro-1-(2-hydroxyethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate.
  • the 2-hydroxy ethyl derivative thus obtained, without further purification, was dissolved in 100 ml of chloroform.
  • the solution was mixed with 6.2g of thionyl chloride and the mixture was heated to reflux for 50 minutes.
  • To the reaction mixture was added ethanol and water to decompose an excess of thionyl chloride.
  • Compounds 1 to 4, especially compounds 1, 1' and 2, of this invention exhibit very high antibacterial activities against Gram-positive bacteria and Gram-negative bacteria including Pseudomonas aeruginosa.
  • Compound A (6-unsubstituted 1,8-naphthyridine) has much inferior antibacterial activity against Gram-positive and Gram-negative bacteria to the compounds of the present invention.
  • mice Male mice (ddY) weighing about 20 g Infection:
  • Compounds 1 and 1' of this invention show potent therapeutic effects on the systemic infections with Gram-positive and Gram-negative bacteria.
  • compound 2 of this invention against infections with Gram-positive bacteria is inferior to that of compound 1 or 1', but its therapeutic effect against infections witn Gram-negative bacteria is superior.
  • the compound 2 of the invention is especially useful for the treatment of systemic infection caused by Pseudomonas acruginosa.
  • Compounds 1, 1' and 2 of this invention exhibit better therapeutic effects against systemic infection with Gram-negative bacteria, especially Pseudomona s aeruginosa, than compounds A and C, compounds E and F which are commercially available synthetic antibacterial agents, and compounds G, H and J which are commercially available antibiotics.
  • Compounds 1 and 1' of this invention are clearly superior in therapeutic effect in vivo against Gram-positive bacteria to compound D.
  • Compounds 1, 1' and 2 of this invention are clearly better than compound D in therapeutic effect in vivo against Gram-negative bacteria including Pseudomonas aeruginosa.
  • the ethyl ester of compound 1 of this invention is useful as an intermediate for the synthesis of compounds 1 and 1' of this invention. It also has superior antibacterial activity in vivo against Gram-positive bacteria and Gram-negative bacteria.
  • mice Female nice (ddY-S) weighing 22 to 30 g were anesthetized by intravenous injection of sodium pento- barbital at a dose of 50 mg/kg. Through a small suprapubic incision, the urinary bladder was exposed and then infected by injecting 0.1 ml of a 1:10,000 dilution of Pseudomonas aeruginosa No. 12 cultured for 20 hours in trypto-soybroth, using 0.25 ml syringe with 0.25 mm needle. The mice were restrained from drinking water for a period from 1 day before to 1 day after the infection and treated twice a day for 3 days starting on the day of infection.
  • kidneys were harvested for the detection of the bacteria, transversely bisected and stamped on King A Agar, which were incubated at 37°C overnight. No bacterial finding in the kidneys was regarded as protected from the ascending kidney infection. ED 50 values were calculated by probit analysis.
  • a solution containing each of compounds 1 to 4 and compounds B to J in various concentrations was orally given to male mice (ddY) (4 to 8 in each group) at a dose of 0.1 ml per 10 g of body weight.
  • the number of dead mice was counted after 7 days, and the value of median lethal dose (LD 50 , ng/kg) was calculated in accordance with the Behrens-Kaerber method. The results are shown in Table IV.
  • Compound 1 was orally administered to six female mice (JCL-ICR strain) having an average body weight of 20g at a dose of 2g/kg once a day for 14 days. During the test period, the body weight of each mouse was measured. On the 15th day, the mice were henatologically examined. After the hematological examination, the mice were sacrificed, and the organs were weighed and histo- pathologically observed. Consequently, the following facts were found out.
  • Drug levels were determined by the thin-layer cup-plate method using Escherichia coli Kp as an indicator organism.
  • Compounds 1 and 2 of this invention are well absorbed in the body by oral administration, and are maintained at a high level in the plasma for a fairly long time.
  • compound 1 shows a plasma level higher than the MIC values (see Table I) against most bacteria over a period of 1 to 10 hours after administration.
  • Compound 2 shows the same plasma level over a period of at least 2 hours to even more than 10 hours after administration.
  • the plasma level (5.9 ⁇ g/ml) of compound 1 is about 8 times the MIC values against Pseudomonas aeruginosa No. 12 and Staphylococcus aureus No. 50774, and amounts to about 60 times the MIC value against Eschcrichia coli P-5101.
  • Example F The urine excreted by the dogs used in Example F was pooled over a period of 24 hours, and compound 1 or 2 in the pooled urine was determined by the same method as in Example F. The results are shown in Table VI.
  • compounds 1 and 2 of this invention exhibit superior effects at low dosages in the treatment of urinary tract infection caused by various bacteria.
  • the compounds of this invention exhibit a superior therapeutic effect on the experimental infections with Gram-positive and Gram-negative bacteria and after oral administration they maintain high plasma and urinary levels for a fairly long time. Moreover, they have low toxicity. Accordingly, these compounds are effective at low dosages for the treatment of urinary tract infection and systemic infection caused by various bacteria.
  • Compound D is clearly inferior to compounds 1, 1' and 2 of this invention in therapeutic efficacy (see Table III) against ascending kidney infection with Pseudomonas aeruginosa.
  • Nalidixic acid (compound E) and Pipemidic acid (compound F), which are commercially available synthetic antibacterial agents, and Carindacillin (compound G), Ampicillin (compound H) and Cephalexin (compound J) which are commercially available antibiotics are clearly inferior to the compounds 1, 1' and 2 of this invention in therapeutic effects (see Table II) in vivo against Gram-negative bacteria, particularly Pseudomonas aeruginosa.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
EP79400587A 1978-08-25 1979-08-24 Dérivés de la naphtyridine et compositions pharmaceutiques les contenant Expired EP0009425B1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
JP10423578A JPS5531042A (en) 1978-08-25 1978-08-25 1,8-naphthylidine derivative and its salt
JP104235/78 1978-08-25
JP157939/78 1978-12-20
JP15793978A JPS5583785A (en) 1978-12-20 1978-12-20 6-fluoro-1,8-naphthyridine derivative and its salt
JP16209578A JPS5592385A (en) 1978-12-29 1978-12-29 1-vinyl-1,8-naphthylidine derivative and its salt
JP162095/78 1978-12-29

Publications (2)

Publication Number Publication Date
EP0009425A1 true EP0009425A1 (fr) 1980-04-02
EP0009425B1 EP0009425B1 (fr) 1982-01-27

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EP79400587A Expired EP0009425B1 (fr) 1978-08-25 1979-08-24 Dérivés de la naphtyridine et compositions pharmaceutiques les contenant

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US (2) US4359578A (fr)
EP (1) EP0009425B1 (fr)
AR (3) AR223983A1 (fr)
AU (1) AU530052B2 (fr)
CA (1) CA1168241A (fr)
CS (1) CS235502B2 (fr)
DD (1) DD145753A5 (fr)
DE (1) DE2961979D1 (fr)
DK (1) DK153552C (fr)
ES (1) ES483629A1 (fr)
FI (1) FI66379C (fr)
HU (1) HU179927B (fr)
NO (1) NO153136C (fr)
PH (1) PH14287A (fr)
PL (1) PL120114B1 (fr)
YU (4) YU42193B (fr)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0027752A1 (fr) * 1979-09-28 1981-04-29 Société anonyme dite: LABORATOIRE ROGER BELLON Dérivés de la naphtyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
FR2496663A1 (fr) * 1980-12-24 1982-06-25 Bellon Labor Sa Roger Nouveaux derives de naphtyridine-1,8 utiles notamment comme medicaments antibacteriens
EP0058614A1 (fr) * 1981-02-13 1982-08-25 Société anonyme dite: LABORATOIRE ROGER BELLON Sesquihydrate de l'acide 1-éthyl-6-fluoro-1,4-dihydro-4-oxo-7(1-pipérazinyl)1,8-naphthyridine carboxylique, procédé de préparation et utilisation comme bactéricide
EP0067666A1 (fr) * 1981-06-11 1982-12-22 Warner-Lambert Company Sels de composés microbicides de naphtyridine et quinoléine et leur préparation
FR2531084A1 (fr) * 1982-07-30 1984-02-03 Bellon Labor Sa Roger Nouveaux derives de la 7-(4-pyridyl)-1,8-naphtyridine, medicament et compositions pharmaceutiques en contenant
FR2548664A1 (fr) * 1983-07-06 1985-01-11 Provesan Sa Derives 7-(pyrrol-l-yl) des acides l-ethyl-1,4-dihydro-4-oxoquinoleine-3-carboxyliques et l-ethyl-1,4-dihydro-4-oxo-(1,8-naphtyridine)-3-carboxyliques substitues, leur preparation et leur application en tant que medicaments
EP0134165A2 (fr) * 1983-07-06 1985-03-13 Provesan S.A. Dérivés 7-(pyrrol-1-yl) des acides 1-éthyl-1,4-dihydro-4-oxoquinoléine-3-carboxyliques et 1-éthyl-1,4-dihydro-4-oxo-(1,8-naphtyridine)-3-carboxyliques substitués, leur préparation et leur application en tant que médicaments
EP0138018A2 (fr) * 1983-09-17 1985-04-24 Bayer Ag Solutions de sels de l'acide lactique des acides pipérazinylquinolonecarboxyliques et pipérazinylazaquinolonecarboxyliques
EP0142426A2 (fr) * 1983-11-14 1985-05-22 Merck & Co. Inc. Formulation ophtalmique contenant de la norfloxacine et antibiotiques apparentés
EP0153580A1 (fr) * 1984-01-26 1985-09-04 Abbott Laboratories Composés antibactériaux de naphthyridine
EP0153828A2 (fr) * 1984-02-17 1985-09-04 Warner-Lambert Company Acides 1 cyclopropyl-1,4, dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxyliques, leurs dérivés et procédé pour leur préparation
EP0155587A1 (fr) * 1984-03-17 1985-09-25 Bayer Ag Acides diamino-1,7 dihydro-1,4 oxo-4(aza)quinoléine-carboxyliques-3, procédé pour leur préparation et leur application dans le traitement de maladies bactériennes
EP0159174A2 (fr) * 1984-04-16 1985-10-23 Warner-Lambert Company Acides carboxyliques substitués de la naphtyridine, quinoléine et benzoxazine comme agents bactéricides et procédés pour leur préparation
EP0205029A2 (fr) * 1985-06-07 1986-12-17 Bayer Ag Acides quinoléine carboxyliques à activité bactéricide
EP0210513A1 (fr) * 1985-07-24 1987-02-04 Bayer Ag Préparations pour le traîtement des mycoplasmoses et des infections bactériennes chez la volaille
US4670444A (en) * 1980-09-03 1987-06-02 Bayer Aktiengesellschaft 7-amino-1-cyclopropyl-4-oxo-1, 4-dihydro-quinoline-and naphthyridine-3-carboxylic acids and antibacterial agents containing these compounds
US4687770A (en) * 1985-12-23 1987-08-18 Abbott Laboratories Isoxazolo-pyrido-benzoxazine and isothiazolo-pyrido-benzoxazine derivatives
US4689325A (en) * 1985-12-23 1987-08-25 Abbott Laboratories Isoxazolo-pyrido-phenoxazine and isothiazolo-pyrido-phenoxazine derivatives
US4704459A (en) * 1985-01-23 1987-11-03 Toyama Chemical Co., Ltd. Process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives, and processes for producing the intermediates
US4730000A (en) * 1984-04-09 1988-03-08 Abbott Laboratories Quinoline antibacterial compounds
EP0279241A1 (fr) * 1987-01-28 1988-08-24 Warner-Lambert Company Compositions ophthalmiques stabilisées
US4851535A (en) * 1985-01-23 1989-07-25 Toyama Chemical Co., Ltd. Nicotinic acid derivatives
AT389698B (de) * 1984-04-26 1990-01-10 Toyama Chemical Co Ltd Verfahren zur herstellung von neuen 1,4-dihydro-4-oxonaphthyridin-derivaten und deren salzen
EP0350950A1 (fr) * 1988-07-15 1990-01-17 Abbott Laboratories Procédé pour la préparation des composés antibactériens de quinoline
FR2641783A1 (fr) * 1989-01-16 1990-07-20 Bellon Labor Sa Roger Nouveaux derives de benzonaphtyridine-1,8, leur preparation et les compositions qui les contiennent
EP0379412A1 (fr) * 1989-01-16 1990-07-25 Société anonyme dite: LABORATOIRE ROGER BELLON Dérivés de benzonaphtyridine-1,8 leur préparation et les compositions qui les contiennent
AT392791B (de) * 1985-01-23 1991-06-10 Toyama Chemical Co Ltd Verfahren zur herstellung von 1-substituierten aryl-1,4-dihydro-4-oxonaphthyridinderivaten
US5077429A (en) * 1980-09-03 1991-12-31 Bayer Aktiengesellschaft 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline- and naphthyridine-3-carboxylic acids, processes for their preparation and antibacterial agents containing these compounds
US5498615A (en) * 1993-04-24 1996-03-12 Korea Research Institute Of Chemical Technology Quinolone carboxylic acid derivatives and process for preparing the same
US5817820A (en) * 1993-12-09 1998-10-06 Korea Research Institute Of Chemical Technology Quinolone derivatives and processes for the preparation thereof
US7700617B2 (en) 1997-03-21 2010-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative

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JPS5845426B2 (ja) * 1978-09-29 1983-10-08 杏林製薬株式会社 置換キノリンカルボン酸誘導体
DE3308908A1 (de) * 1983-03-12 1984-09-13 Bayer Ag, 5090 Leverkusen Bakterizide mittel
CS274601B2 (en) * 1983-07-27 1991-09-15 Dainippon Pharmaceutical Co Method of 1,8-naphthyridine derivative production
US4774246A (en) * 1984-01-26 1988-09-27 Abbott Laboratories Quinoline antibacterial compounds
DE3420743A1 (de) * 1984-06-04 1985-12-05 Bayer Ag, 5090 Leverkusen 7-amino-1-cyclopropyl-6,8-dihalogen-1,4-dihydro-4-oxo-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
US5468861A (en) * 1984-06-04 1995-11-21 Bayer Aktiengesellschaft 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and alkyl esters thereof
DE3517709A1 (de) * 1985-01-05 1986-07-10 Bayer Ag Basische zubereitungen von chinoloncarbonsaeuren
DE3508816A1 (de) * 1985-01-10 1986-07-10 Bayer Ag, 5090 Leverkusen 6,7-disubstituierte 1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphtyridin-3-carbonsaeuren
DE3542002A1 (de) * 1985-11-28 1987-06-04 Bayer Ag 1-cyclopropyl-6-fluor-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-chinolincarbonsaeuren, verfahren zu ihrer herstellung sowie diese enthaltende antibakterielle mittel
US4940710A (en) * 1986-01-17 1990-07-10 American Cyanamid Company 7-(substituted)piperazinyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
US5210193A (en) * 1986-01-17 1993-05-11 American Cyanamid Company Piperazine derivatives
HU196987B (en) * 1986-10-15 1989-02-28 Chinoin Gyogyszer Es Vegyeszet Process for producing quinoline-carboxylic acid derivatives
IL80459A (en) * 1986-10-30 1991-04-15 Abic Ltd Water-soluble adduct of norfloxacin and nicotinic acid
US5262417A (en) * 1988-12-06 1993-11-16 The Upjohn Company Antibacterial quinolone compounds
US5466696A (en) * 1992-09-10 1995-11-14 Warner Lambert Company Tacrine and cytochrome P450 oxidase inhibitors and methods of use
US5422350A (en) * 1992-09-10 1995-06-06 Warner-Lambert Company Nitrogen substituted acridine and cytochrome P450 inhibitors and methods of use
US5290794A (en) * 1992-10-27 1994-03-01 Warner Lambert Co. Soluble calcium lactate antibacterial complexes as non-irritating parenteral forms

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Cited By (47)

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Publication number Priority date Publication date Assignee Title
EP0027752A1 (fr) * 1979-09-28 1981-04-29 Société anonyme dite: LABORATOIRE ROGER BELLON Dérivés de la naphtyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
US5077429A (en) * 1980-09-03 1991-12-31 Bayer Aktiengesellschaft 7-amino-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline- and naphthyridine-3-carboxylic acids, processes for their preparation and antibacterial agents containing these compounds
US4670444A (en) * 1980-09-03 1987-06-02 Bayer Aktiengesellschaft 7-amino-1-cyclopropyl-4-oxo-1, 4-dihydro-quinoline-and naphthyridine-3-carboxylic acids and antibacterial agents containing these compounds
FR2496663A1 (fr) * 1980-12-24 1982-06-25 Bellon Labor Sa Roger Nouveaux derives de naphtyridine-1,8 utiles notamment comme medicaments antibacteriens
US4496566A (en) * 1980-12-24 1985-01-29 Dainippon Pharmaceutical Co., Ltd. Naphthyridine derivatives
EP0058614A1 (fr) * 1981-02-13 1982-08-25 Société anonyme dite: LABORATOIRE ROGER BELLON Sesquihydrate de l'acide 1-éthyl-6-fluoro-1,4-dihydro-4-oxo-7(1-pipérazinyl)1,8-naphthyridine carboxylique, procédé de préparation et utilisation comme bactéricide
EP0067666A1 (fr) * 1981-06-11 1982-12-22 Warner-Lambert Company Sels de composés microbicides de naphtyridine et quinoléine et leur préparation
FR2531084A1 (fr) * 1982-07-30 1984-02-03 Bellon Labor Sa Roger Nouveaux derives de la 7-(4-pyridyl)-1,8-naphtyridine, medicament et compositions pharmaceutiques en contenant
EP0134165A3 (en) * 1983-07-06 1985-10-09 Provesan S.A. 7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 7-(pyrrol-1-yl)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid derivatives, their preparation and use as medicaments
FR2548664A1 (fr) * 1983-07-06 1985-01-11 Provesan Sa Derives 7-(pyrrol-l-yl) des acides l-ethyl-1,4-dihydro-4-oxoquinoleine-3-carboxyliques et l-ethyl-1,4-dihydro-4-oxo-(1,8-naphtyridine)-3-carboxyliques substitues, leur preparation et leur application en tant que medicaments
EP0134165A2 (fr) * 1983-07-06 1985-03-13 Provesan S.A. Dérivés 7-(pyrrol-1-yl) des acides 1-éthyl-1,4-dihydro-4-oxoquinoléine-3-carboxyliques et 1-éthyl-1,4-dihydro-4-oxo-(1,8-naphtyridine)-3-carboxyliques substitués, leur préparation et leur application en tant que médicaments
FR2559484A2 (fr) * 1983-07-06 1985-08-16 Provesan Sa Nouveau derive 7-(pyrrol-1-yl) de l'acide 1-ethyl-1,4-dihydro-4-oxo-(1,8-naphtyridin)-3-carboxylique, sa preparation et son application en tant que medicament
US4808585A (en) * 1983-09-17 1989-02-28 Bayer Aktiengesellschaft Solutions of lactic acid salts of piperazinylquinolone- and piperazinyl-azaquinolone-carboxylic acids
EP0138018A2 (fr) * 1983-09-17 1985-04-24 Bayer Ag Solutions de sels de l'acide lactique des acides pipérazinylquinolonecarboxyliques et pipérazinylazaquinolonecarboxyliques
US4808583A (en) * 1983-09-17 1989-02-28 Bayer Aktiengesellschaft Solutions of lactic acid salts of piperazinylquinolone- and piperazinyl-azaquinolone-carboxylic acids
EP0138018B1 (fr) * 1983-09-17 1988-11-02 Bayer Ag Solutions de sels de l'acide lactique des acides pipérazinylquinolonecarboxyliques et pipérazinylazaquinolonecarboxyliques
US4705789A (en) * 1983-09-17 1987-11-10 Bayer Aktiengesellschaft Solutions of lactic acid salts of piperazinylquinolone- and piperazinyl-azaquinolone-carboxylic acids
EP0142426A2 (fr) * 1983-11-14 1985-05-22 Merck & Co. Inc. Formulation ophtalmique contenant de la norfloxacine et antibiotiques apparentés
EP0142426A3 (fr) * 1983-11-14 1986-12-17 Merck & Co. Inc. Formulation ophtalmique contenant de la norfloxacine et antibiotiques apparentés
EP0153580A1 (fr) * 1984-01-26 1985-09-04 Abbott Laboratories Composés antibactériaux de naphthyridine
EP0153828A2 (fr) * 1984-02-17 1985-09-04 Warner-Lambert Company Acides 1 cyclopropyl-1,4, dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxyliques, leurs dérivés et procédé pour leur préparation
EP0153828A3 (en) * 1984-02-17 1985-10-16 Warner-Lambert Company 1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids; 1-cyclopropyl-1, 4-dihydro-6-fluoro-4-oxo-1, 8-naphthyridine-3-carboxylic acids; their derivatives and a process for preparing the compounds
US4753925A (en) * 1984-03-17 1988-06-28 Bayer Aktiengesellschaft Antibacterial 1,7-diamino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
EP0155587A1 (fr) * 1984-03-17 1985-09-25 Bayer Ag Acides diamino-1,7 dihydro-1,4 oxo-4(aza)quinoléine-carboxyliques-3, procédé pour leur préparation et leur application dans le traitement de maladies bactériennes
US4666920A (en) * 1984-03-17 1987-05-19 Bayer Aktiengesellschaft Antibacterial 1,7-diamino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids
US4730000A (en) * 1984-04-09 1988-03-08 Abbott Laboratories Quinoline antibacterial compounds
EP0159174A2 (fr) * 1984-04-16 1985-10-23 Warner-Lambert Company Acides carboxyliques substitués de la naphtyridine, quinoléine et benzoxazine comme agents bactéricides et procédés pour leur préparation
EP0159174A3 (en) * 1984-04-16 1987-02-04 Warner-Lambert Company Substituted naphthyridine-, quinoline- and benzoxazine- carboxylic acids as antibacterial agents and processes for their production
AT389698B (de) * 1984-04-26 1990-01-10 Toyama Chemical Co Ltd Verfahren zur herstellung von neuen 1,4-dihydro-4-oxonaphthyridin-derivaten und deren salzen
AT390258B (de) * 1984-04-26 1990-04-10 Toyama Chemical Co Ltd Verfahren zur herstellung von neuen 1,4-dihydro-4-oxonaphthydridin-derivaten und deren salzen
AT392791B (de) * 1985-01-23 1991-06-10 Toyama Chemical Co Ltd Verfahren zur herstellung von 1-substituierten aryl-1,4-dihydro-4-oxonaphthyridinderivaten
AT392789B (de) * 1985-01-23 1991-06-10 Toyama Chemical Co Ltd Verfahren zur herstellung von 1-substituierten aryl-1,4-dihydro-4-oxonaphthyridinderivaten
US4851535A (en) * 1985-01-23 1989-07-25 Toyama Chemical Co., Ltd. Nicotinic acid derivatives
US4704459A (en) * 1985-01-23 1987-11-03 Toyama Chemical Co., Ltd. Process for producing 1-substituted aryl-1,4-dihydro-4-oxonaphthyridine derivatives, and processes for producing the intermediates
EP0205029A3 (fr) * 1985-06-07 1988-06-15 Bayer Ag Acides quinoléine carboxyliques à activité bactéricide
EP0205029A2 (fr) * 1985-06-07 1986-12-17 Bayer Ag Acides quinoléine carboxyliques à activité bactéricide
US5145853A (en) * 1985-07-24 1992-09-08 Bayer Aktiengesellschaft Bactericidal formulations for use in veterinary medicine
EP0210513A1 (fr) * 1985-07-24 1987-02-04 Bayer Ag Préparations pour le traîtement des mycoplasmoses et des infections bactériennes chez la volaille
US4687770A (en) * 1985-12-23 1987-08-18 Abbott Laboratories Isoxazolo-pyrido-benzoxazine and isothiazolo-pyrido-benzoxazine derivatives
US4689325A (en) * 1985-12-23 1987-08-25 Abbott Laboratories Isoxazolo-pyrido-phenoxazine and isothiazolo-pyrido-phenoxazine derivatives
EP0279241A1 (fr) * 1987-01-28 1988-08-24 Warner-Lambert Company Compositions ophthalmiques stabilisées
EP0350950A1 (fr) * 1988-07-15 1990-01-17 Abbott Laboratories Procédé pour la préparation des composés antibactériens de quinoline
EP0379412A1 (fr) * 1989-01-16 1990-07-25 Société anonyme dite: LABORATOIRE ROGER BELLON Dérivés de benzonaphtyridine-1,8 leur préparation et les compositions qui les contiennent
FR2641783A1 (fr) * 1989-01-16 1990-07-20 Bellon Labor Sa Roger Nouveaux derives de benzonaphtyridine-1,8, leur preparation et les compositions qui les contiennent
US5498615A (en) * 1993-04-24 1996-03-12 Korea Research Institute Of Chemical Technology Quinolone carboxylic acid derivatives and process for preparing the same
US5817820A (en) * 1993-12-09 1998-10-06 Korea Research Institute Of Chemical Technology Quinolone derivatives and processes for the preparation thereof
US7700617B2 (en) 1997-03-21 2010-04-20 Lg Life Sciences, Ltd. Salt of naphthyridine carboxylic acid derivative

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YU42193B (en) 1988-06-30
YU203279A (en) 1985-10-31
YU31985A (en) 1985-10-31
YU42614B (en) 1988-10-31
FI792645A (fi) 1980-02-26
YU31785A (en) 1985-10-31
AU530052B2 (en) 1983-06-30
DK153552C (da) 1988-12-05
ES483629A1 (es) 1980-09-01
PL120114B1 (en) 1982-02-27
HU179927B (en) 1983-01-28
PL217926A1 (fr) 1980-06-16
DK355679A (da) 1980-02-26
YU42615B (en) 1988-10-31
NO792760L (no) 1980-02-26
US4352803A (en) 1982-10-05
CS235502B2 (en) 1985-05-15
AR223983A1 (es) 1981-10-15
YU42637B (en) 1988-10-31
AU5004979A (en) 1980-02-28
AR227529A1 (es) 1982-11-15
NO153136C (no) 1986-01-22
DD145753A5 (de) 1981-01-07
NO153136B (no) 1985-10-14
AR225195A1 (es) 1982-02-26
DK153552B (da) 1988-07-25
YU31885A (en) 1985-10-31
EP0009425B1 (fr) 1982-01-27
PH14287A (en) 1981-05-04
FI66379B (fi) 1984-06-29
FI66379C (fi) 1984-10-10
DE2961979D1 (en) 1982-03-11
US4359578A (en) 1982-11-16
CA1168241A (fr) 1984-05-29

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